1. Technical Field of the Invention:
The present invention relates to novel biaromatic compounds, which are modulators of peroxisome proliferator-activated receptors, known as PPAR. This invention also relates to processes for the preparation thereof and to their formulation into pharmaceutical compositions for administration in human or veterinary medicine, or alternatively for inclusion in cosmetic compositions.
2. Description of Background and/or Related and/or Prior Art:
Peroxisome proliferator-activated receptors (PPAR) belong to the superfamily of hormonal nuclear receptors (Mangelsdorf, D. J. et al. Cell, 1995, 83, 841-850). After activation by a ligand, these proteins act as transcription factors and regulate many physiological phenomena, such as reproduction, growth, differentiation, development, metabolic energy and homeostasis. The PPAR subfamily (Kliewer, S. A. et al. Nature, 1992, 358, 771-774; Hertz, R. et al. J. Eur. J. Biochem., 1996, 235, 242-247; Devchand, P. R. et al. Nature 1996, 384, 39-43; Spiegelman, B. M. Cell 1998, 93, 153-155; Kliewer, S. A. et al. Science 1999, 284, 757-760; Willson, T. M. et al., 2000, 43, 527-550) comprises three isoforms (α, γ and 6), which have different tissue distributions and exert different physiological functions, and serve as food lipid sensors for controlling carbohydrate and fatty acid metabolism (Willson, T. M. et al. J. Med. Chem., 2000, 43, 527-550). The PPARα receptors are mainly expressed in the liver, and, after binding with one of their ligands, for example a fibrate, stimulate lipid metabolization.
The PPARγ receptors are strongly expressed in adipocyte tissue, and activate adipogenesis, when they are bound to their natural ligands [(S)-15-deoxy-Δ12.14-PGJ2] or synthetic ligands (thiazolidinediones or glitazones). Among these two, the α and γ isoforms regulate the balance from the catabolism and the storage of the long chains of fatty acids. Interestingly, the PPARδ isoform, which is widely expressed in the brain, the colon and the skin, is a potential transcription repressor (Oliver, W. R. et al. Proc. Natl. Acad. Sci., USA 2001, 98, 5306-5311), which inhibits the transcriptional activity induced by the α and γ isoforms. The role of the PPARδ receptors on anti-lipid oxidation and anti-adipogenesis opens important and promising perspectives for the therapeutic control of obesity and type II diabetes.
One series of fatty acids and of eicosanoids binds to and activates the PPARγ receptors at micromolar concentrations. In contrast with the PPARα receptor, the PPARγ receptor preferentially binds to polyunsaturated fatty acids, such as linoleic acid, linolenic acid, arachidonic acid and eicosapentaenoic acid (EPA).
It has especially been described in WO 96/33724 that PPARγ-selective compounds, such as a prostaglandin-J2 or -D2, are potential active agents for the treatment of obesity and diabetes.
Moreover, the assignee hereof has already described in WO 02/12210 and WO 03/055867 the use of biaromatic compounds that activate PPARγ type receptors in the preparation of a pharmaceutical composition, the composition being intended for treating skin disorders associated with an anomaly of epidermal cell differentiation.
Nevertheless, need continues to exist for such novel compounds that have good activity and advantageous pharmaceutical properties.